Effects of Antiepileptic Drug Monotherapy on One-Carbon Metabolism and DNA Methylation in Patients with Epilepsy

Ni, Guanzhong; Qin, Jiaming; Li, Hongliang; Chen, Ziyi; Zhou, Yifei; Fang, Ziyan; Chen, Yishu; Zhou, Jueqian; Huang, Min; Zhou, Liemin

doi:10.1371/journal.pone.0125656

Cited by 24 publications

(23 citation statements)

References 33 publications

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“… 36 Low serum folate concentrations have been reported after lamotrigine therapy. 37 Impaired neurodevelopment after lamotrigine exposure in utero has been discussed, but data have been conflicting. 38 , 39 A particularly beneficial effect of periconceptional folic acid supplementation on language function in lamotrigine-exposed children is possible and could explain previous discordant results.…”

Section: Discussionmentioning

confidence: 99%

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Verbal abilities in children of mothers with epilepsy

et al. 2018

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ObjectiveTo examine the effect of maternal folic acid supplementation and maternal plasma folate and antiepileptic drug (AED) concentrations on language delay in AED-exposed children of mothers with epilepsy.MethodsChildren of mothers with and without epilepsy enrolled from 1999 to 2008 in the Norwegian Mother and Child Cohort study were included. Information on medical history, AED use, and folic acid supplementation during pregnancy was collected from parent-completed questionnaires. Maternal plasma folate and maternal plasma and umbilical cord AED concentrations were measured in blood samples from gestational weeks 17 to 19 and immediately after birth, respectively. Language development at 18 and 36 months was evaluated by the Ages and Stages Questionnaires.ResultsA total of 335 AED-exposed children of mothers with epilepsy and 104,222 children of mothers without epilepsy were surveyed. For those with no maternal periconceptional folic acid supplementation, the fully adjusted odds ratio (OR) for language delay in AED-exposed children compared to the controls at 18 months was 3.9 (95% confidence interval [CI] 1.9–7.8, p < 0.001) and at 36 months was 4.7 (95% CI 2.0–10.6, p < 0.001). When folic supplementation was used, the corresponding ORs for language delay were 1.7 (95% CI 1.2–2.6, p = 0.01) and 1.7 (95% CI 0.9–3.2, p = 0.13), respectively. The positive effect of folic acid supplement use on language delay in AED-exposed children was significant only when supplement was used in the period from 4 weeks before the pregnancy and until the end of the first trimester.ConclusionFolic acid use early in pregnancy may have a preventive effect on language delay associated with in utero AED exposure.

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Section: Discussionmentioning

confidence: 99%

“… 41 , 42 Folic acid dose recommendations cannot yet be specified for individual AEDs, although several AEDs interact with folic acid metabolism. 4 , 5 , 37 …”

Section: Discussionmentioning

confidence: 99%

Verbal abilities in children of mothers with epilepsy

et al. 2018

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“…(He et al 2014 ; O’Neill et al 2011 ; Quinn and O’Neill 2011 ; van Scheppingen et al 2016 ). Finally, since patients received several antiepileptic drugs, such as valproic acid, a possible effect of drug treatment on DNA methylation patterns (Ni et al 2015 ), as well as on IL-1β expression (Gomez et al 2014 ; Verrotti et al 2001 ), has to be taken into consideration in the interpretation of the expression data in TSC brain specimens.…”

Section: Discussionmentioning

confidence: 99%

Promoter-Specific Hypomethylation Correlates with IL-1β Overexpression in Tuberous Sclerosis Complex (TSC)

et al. 2016

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In tuberous sclerosis complex (TSC), overexpression of numerous genes associated with inflammation has been observed. Among different proinflammatory cytokines, interleukin-1β (IL-1β) has been shown to be significantly involved in epileptogenesis and maintenance of seizures. Recent evidence indicates that IL-1β gene expression can be regulated by DNA methylation of its promoter. In the present study, we hypothesized that hypomethylation in the promoter region of the IL-1β gene may underlie its overexpression observed in TSC brain tissue. Bisulfite sequencing was used to study the methylation status of the promoter region of the IL-1β gene in TSC and control samples. We identified hypomethylation in the promoter region of the IL-1β gene in TSC samples. IL-1β is overexpressed in tubers, and gene expression is correlated with promoter hypomethylation at CpG and non-CpG sites. Our results provide the first evidence of epigenetic modulation of the IL-1β signaling in TSC. Thus, strategies that target epigenetic alterations could offer new therapeutic avenues to control the persistent activation of interleukin-1β-mediated inflammatory signaling in TSC brain.

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“…Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in OCM because it reduces N5,10-methylenetetrahydrofolate to methyltetrahydrofolate, which can affect the DNA methylation process. In addition, methylation status of the MTHFR amplicon was shown to correlate with serum folate levels, indicating that AEDs may have an effect on methylation by reducing folate levels [ 24 ]. Another study showed that VPA-treated patients had both higher serum homocysteine and vitamin B12 levels, which can both affect the OCM [ 25 ].…”

Section: The Epigenetic Effects Of Antiepileptic Drugsmentioning

confidence: 99%

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

Kong

Zhong

2020

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An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.

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Effects of Antiepileptic Drug Monotherapy on One-Carbon Metabolism and DNA Methylation in Patients with Epilepsy

Cited by 24 publications

References 33 publications

Verbal abilities in children of mothers with epilepsy

Verbal abilities in children of mothers with epilepsy

Promoter-Specific Hypomethylation Correlates with IL-1β Overexpression in Tuberous Sclerosis Complex (TSC)

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

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